The purpose of this research is to investigate how persons with, or at risk for, HIV recover from hepatitis C virus (HCV) infection. HCV infection is one of the two leading causes of death in persons with HIV, especially those who acquired HIV from illicit drug use. HCV infection resolves spontaneously in some persons, but recovery occurs less in those with HIV. There is a strong host genetic basis for HIV outcome differences and at least one HLA allele appears also to influence recovery from hepatitis C. By comparing the DNA from persons who recovered from hepatitis C with DNA from those with viral persistence, the host genetic basis is explored. In a large DNA testing panel, genetic associations are independently confirmed and assessed according to race. For strong, confirmed genetic associations, the biologic basis is studied to understand the mechanism. Effort in the next grant cycle builds on the strongest preliminary findings focusing on key elements of the immune response including human leukocyte antigen - C and interleukin 18. Innovative approaches are employed including searching for the explanation for why the same HLA allele would affect HIV and HCV infections, as well as analyzing interactions between genes and investigating the immunologic basis. By showing how the DNA of humans who recover from viral illness differs from those who get chronic infection, this research will provide clues as to better ways to prevent and treat chronic infectious diseases. This information will be especially helpful in efforts to combat HIV and HCV infections, which are leading causes of morbidity and mortality worldwide. PUBLIC HEALTH RELEVANCE: Hepatitis C is one of the leading causes of death among persons with HIV. This project investigates persons with HIV infection and those at risk for HIV infection and asks why they recover from hepatitis C. Specifically, DNA for genes that encode for immune responses are compared and laboratory experiments are done to understand the biologic basis for key findings. There is a special focus on genes that appear to affect HIV and other chronic viral infections.